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  • Fmoc-Ala-OH Sonidegib is currently under investigation for t

    2021-11-29

    Sonidegib is currently under investigation for the treatment of relapsed/refractory acute leukemia (NCT01826214) [76]. All patients experienced at least 1 AE, including anemia, diarrhea, fatigue, nausea, muscle spasms, decreased appetite, and blood creatine phosphokinase increased. The ongoing phase 2 trial in patients with AML (NCT01546038) evaluated the safety of G+LDAC [42]. The most frequently reported nonhematologic grade 3/4 AEs in the G+LDAC group included pneumonia, fatigue, dyspnea, hyponatremia, sepsis, and syncope; and pneumonia in the LDAC group [42]. Furthermore, the frequency of AEs commonly associated with SMO inhibitors (ie, alopecia, muscle spasms, and dysgeusia) was lower in the G+LDAC-treated patients [42]. The combination of G+LDAC was well tolerated and exhibited a manageable safety profile; results indicate that G+LDAC may be a suitable therapeutic strategy for intensive chemotherapy ineligible patients with AML [42].
    Biomarkers of Response to Hedgehog Inhibitors It is important to determine which patients may be more responsive to HHI therapy. Previous studies aimed to identify biomarkers to pinpoint those more likely to exert a pharmacodynamic effect in response to HHI treatment [77]. Vismodegib exhibited activity in adult recurrent SHH-medulloblastoma patients but not in those with recurrent non–SHH-medulloblastoma, suggesting that HHI activity depends on genomic abnormality within the tumor [58]. Furthermore, a 5-gene HH signature assay was identified and clinically validated for use in medulloblastoma patients to identify those with HH-activated disease and, therefore, more likely to respond to sonidegib treatment [59]. The 5 differentially expressed genes (GLI1, SPHK1, SHROOM2, PDL1M3, OXT2) showed 100% correlation between HH activation status and gene Fmoc-Ala-OH profiling (n = 25). Moreover, of 50 patients treated with sonidegib, 6 of the 9 patients who had HH-activated tumors responded, while the remaining 3 had stable or progressive disease [59]. Logically, therefore, all 41 patients without HH-activated tumors failed to respond [59]. A phase 1 trial determining the efficacy and safety of sonidegib in advanced solid tumors showed that GLI1 mRNA expression was reduced in tumor and skin posttreatment, suggesting GLI1 expression as a pharmacodynamic marker for HH pathway activation [56]. Despite GLI1 inhibition being dose- and exposure-dependent, the observed decrease did not coincide with tumor response due to a limited sample size [56]. Analysis of GLI1 expression at week 17 in the phase 2 BOLT trial showed a decrease from baseline in patients with disease control [31]. In comparison, in a patient with progressive disease and evaluable tumor, GLI1 expression increased by 10% [31]. HH inhibition was associated with GLI1 inhibition and tumor response, as evidenced by reduced GLI1 expression in patients with disease control [31]. In the previously described phase 2 randomized trial in AML patients (NCT01546038), 21 genes, 38 circulating cytokine analytes, and 109 gene mutations were analyzed [43]. In the G+LDAC-treated patients, improved OS correlated with reduced expression of FOXM1 and MSI2; and higher BCL2 and CCND2 [43]. Furthermore, macrophage inflammatory protein 1-alpha (MIP-1α) cytokine levels were reduced. Inhibition of HH signaling may override the pro-survival benefit of high BCL2 expression; and reduced MIP-1α levels may facilitate glasdegib-induced cell cycle re-entry, coinciding with cell susceptibility to LDAC [43]. No mutations correlated with OS or overall response [43]. However, increased PTCH1 and reduced BAFF expression did correlate with overall response in the G+LDAC-treated patients, suggesting increased HH pathway activity and, therefore, increased dependence on HH signaling. In the glasdegib plus chemotherapy cohort, OS correlated with low IL-8 and MIP-3β/CCL19levels; as well as mutations in CEP170 and ANKRD26 [43]. Since this was a small study with a limited number of patients, further studies are warranted to determine if the biomarker differences observed between the cohorts are treatment related [43]. Additional information regarding biomarker analysis is expected from the ongoing phase 3 trial with glasdegib in patients with previously untreated AML (NCT03416179). Collectively, these studies indicate that molecular and genomic analyses are critical to identify patients that will benefit from targeted HHI therapy [58].